Aminophenols are generally known to be useful as dye intermediates, particularly for the so-called azo and sulfur dyes. Aminophenols are intermediates for pharmaceuticals, such as for amino salicyclic acid or APAP. In addition, aminophenols are used as oil additives, as photographic developers and as antioxidants.
N-acetyl-p-aminophenol (APAP) is a known compound widely used as an analgesic and anti-pyretic agent in various therapeutic preparations. A commercial method for preparing N-acetyl-p-aminophenol involves reduction of p-nitrophenol to p-aminophenol and then acetylation wherein the p-aminophenol is dispersed in a non-aqueous solvent and/or excess anhydride.
The conventional process for the reduction of p-nitrophenol to produce p-aminophenol involves catalytically hydrogenating the p-nitrophenol in the presence of strong acids such as sulfuric, hydrochloric and phosphoric acids as shown in U.S. Pat. No. 2,198,249. Other acids such as oxalic or sulfonic acids as disclosed in U.S. Pat. No. 2,525,515 have also been used. Metal catalysts used for reduction include aluminum as in U.S. Pat. No. 2,525,515; platinum, palladium or noble metal catalysts and their oxides as described in U.S. Pat. Nos. 2,947,781; 3,076,030; 3,079,435; 3,328,465; 3,383,416; 3,654,365 and 3,383,416; and molybdenum sulfide or platinum sulfide-on-carbon as in U.S. Pat. No. 3,953,309.
In all of these methods, the p-aminphenol which is obtained is relatively impure and requires substantial purification before it can be further used in the production of APAP. Unfortunately, by-products are formed in the reduction of the p-nitrophenol and in the acetylation which lead to off-color and impure APAP thus requiring further purification and crystallization steps to produce an acceptable product as described in U.S. Pat. Nos. 3,658,905; 3,694,508; 3,703,598; 3,717,680; 3,845,129; 3,876,703 and 3,953,283.
Attempts to overcome the discoloration and by-product formation by various techniques have not been entirely successful or economical. The use of a reducing atmosphere and non-oxidizing acids is described in U.S. Pat. Nos. 3,177,250; 3,042,719 and 3,223,727. More recently simultaneous reduction of p-nitrophenol and acetylation of the p-aminophenol product while using an acetic acid solvent or acetic anhydride solvent system without prior isolation of the p-aminophenol has been reported as in U.S. Pat. Nos. 3,076,030 and 3,341,587.
The principle method for the preparation of p-nitrophenol begins with nitration and chlorination of benzene to produce p-chloronitrobenzene. The p-chloronitrobenzene then is subjected to alkaline hydrolysis to produce the p-nitrophenol. The p-nitrophenol must be purified and separated from the hydrolysate before it can be used to prepare acceptable APAP according to the conventional processes. Heretofore in the preparation of N-acetyl-p-aminophenol (APAP) it has been necessary to follow expensive and laborious purification procedures for p-nitrophenol, p-aminophenol and the APAP to insure an acceptably pure APAP product for therapeutic preparations.